Multi-modal synchronization therapy

ABSTRACT

The invention provides methods for treating a neurological disorder or deficit, such as tinnitus and phantom limb pain.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/395,034, filed Mar. 30, 2015, which is a 35 U.S.C. § 371 applicationof International Application No. PCT/US2013/026594, filed Feb. 18, 2013,which claims the benefit of priority of U.S. Application Ser. No.61/625,526, filed Apr. 17, 2012. The entire content of the applicationsreferenced above are hereby incorporated by reference herein.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with government support under Grant#R03-DC011589 awarded by the National Institutes of Health. Thegovernment has certain rights in the invention.

BACKGROUND

About 250 million people worldwide experience chronic tinnitus that canbe bothersome on a daily basis. In the U.S. alone, approximately 16million people have sought medical attention for tinnitus, with 2-3million experiencing debilitating and even suicidal conditions (e.g.,related to annoyance, depression, anxiety, headaches, insomnia).Considering the link between tinnitus and hearing loss, these numberswill continue to rise due to increased noise in our environment, alarger elderly population, and greater noise-based war injuries. Infact, tinnitus is currently the highest service-connected disability forveterans and the top war-related health cost. Unfortunately, there is nocure or reliable treatment for tinnitus. Various drug therapies, neuraland mechanical stimulation methods, psychotherapy, and sound treatmentshave been attempted but with mixed results. Accordingly, methods totreat tinnitus are needed.

SUMMARY OF CERTAIN EMBODIMENTS OF THE INVENTION

As described herein, a non-invasive or minimally invasive electricalstimulation treatment for suppressing tinnitus is provided. Thetreatment uses a new approach of simultaneously activating multipleauditory and non-auditory neural pathways with transcutaneous orsubcutaneous surface stimulation as well as sound stimulation to inducea highly synchronous “shock” in specific auditory, non-auditory andmulti-modal brain centers to improve or suppress the subjective perceptof the tinnitus.

Accordingly, certain embodiments of the present invention provide amethod for treating tinnitus in a patient in need of such treatment,comprising delivering to the patient at least one synchronizedstimulation to the brain, wherein the synchronized stimulation comprisesstimulation from at least one auditory pathway and stimulation from atleast one non-auditory pathway.

Certain embodiments of the present invention provide a method fortreating tinnitus in a patient in need of such treatment, comprisingdelivering to the patient at least one synchronized stimulation to thebrain wherein the synchronized stimulation comprises stimulation from atleast two non-auditory pathways.

In certain embodiments, the synchronized stimulation involves a stimuluspattern lasting between 0.01 to 100 ms for each activated pathway with aspecifically determined time between each activated pathway that rangesbetween 0-1000 ms.

In certain embodiments, the non-auditory pathway is a sensory pathwayfrom the patient's head, face, ear, eye, nose, mouth, lip, tongue,tooth, neck, body, limb, genital areas, buttocks/anus regions, hand,finger, foot, or toe.

In certain embodiments, the synchronized stimulation comprisesstimulation of multiple non-auditory pathways of more than 10 sitesacross the patient's head, face, ear, eye, nose, mouth, lip, tongue,tooth, neck, body, limb, genital areas, buttocks/anus regions, hand,finger, foot, or toe to achieve targeted brain activation.

In certain embodiments, the synchronized stimulation comprisesstimulation of multiple non-auditory pathways of more than 100 sitesacross the patient's head, face, ear, eye, nose, mouth, lip, tongue,tooth, neck, body, limb, genital areas, buttocks/anus regions, hand,finger, foot, or toe to achieve targeted brain activation.

In certain embodiments, the synchronized stimulation comprisesstimulation of multiple non-auditory pathways of more than 1000 sitesacross the patient's head, face, ear, eye, nose, mouth, lip, tongue,tooth, neck, body, limb, genital areas, buttocks/anus regions, hand,finger, foot, or toe to achieve targeted brain activation.

In certain embodiments, a single synchronized stimulation is delivered.

In certain embodiments, multiple discrete synchronized stimulations aredelivered 100 to 10000 ms apart for a total duration ranging from 1second to 1 hour that can optionally be repeated as many times as neededfor treatment.

In certain embodiments, the stimulation from the non-auditory pathway isevoked by non-invasive stimulation.

In certain embodiments, the stimulation from the non-auditory pathway isevoked by transcutaneous electrical stimulation.

In certain embodiments, the stimulation from the non-auditory pathway isevoked by vibration, pressure, heat, optics, magnetic, ultrasound, tasteor scent stimulation.

In certain embodiments, the stimulation from the non-auditory pathway isevoked by a single pulse or pulse train.

In certain embodiments, the stimulation from the non-auditory pathway isevoked by a sinusoid.

In certain embodiments, the stimulation from the non-auditory pathway isevoked by a constant or complex shape.

In certain embodiments, the stimulation from the non-auditory pathway isevoked by subcutaneous electrical stimulation.

In certain embodiments, the stimulation from the non-auditory pathway isevoked by epidural, surface, or penetrating cortical stimulation.

In certain embodiments, the stimulation from the non-auditory pathway isevoked by a single pulse or pulse train.

In certain embodiments, the stimulation from the non-auditory pathway isevoked by a sinusoid.

In certain embodiments, the stimulation from the non-auditory pathway isevoked by a constant or complex shape.

In certain embodiments, the synchronized stimulation from the auditorypathway is evoked by sound.

In certain embodiments, the synchronized stimulation from the auditorypathway is evoked by vibration of the head, outer or middle earstructures, cochlea, or head fluids.

In certain embodiments, the synchronized stimulation from the auditorypathway is evoked by one or more pure tone frequencies.

In certain embodiments, the synchronized stimulation from the auditorypathway is evoked by bandwidth filtered sinusoids or noise.

In certain embodiments, the synchronized stimulation from the auditorypathway is evoked by a complex waveform.

In certain embodiments, the synchronized stimulation from the auditorypathway is evoked by electrical stimulation of the auditory nerve.

In certain embodiments, the synchronized stimulation from the auditorypathway is evoked by optical, magnetic, or ultrasound stimulation of theauditory nerve.

In certain embodiments, the synchronized stimulation from the auditorypathway is evoked by electrical stimulation within the brain, includingthe cochlear nucleus, inferior colliculus, medial geniculate, cortex.

In certain embodiments, the synchronized stimulation from the auditorypathway is evoked by optical, magnetic, or ultrasound stimulation withinthe brain, including the cochlear nucleus, inferior colliculus, medialgeniculate, cortex.

In certain embodiments, the synchronized stimulation from the auditorypathway is evoked by non-invasive electrical, magnetic, or ultrasoundcortical stimulation.

In certain embodiments, the synchronized stimulation from the auditorypathway is evoked by epidural, surface, or penetrating corticalstimulation.

In certain embodiments, the stimulation from the auditory pathway isevoked by a single pulse or pulse train.

In certain embodiments, the stimulation from the auditory pathway isevoked by a sinusoid.

In certain embodiments, the stimulation from the auditory pathway isevoked by a constant or complex shape.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Simplified schematic of ascending and descending auditorysystem. CNV, ICC, MGV and A1 are the main ascending auditory nuclei andspatially organized based on sensitivity to different frequencies, whileCNX, ICX, MGX and AX correspond to the outer regions involved withmulti-modal processing. The listed non-auditory pathways project to ICXand other relevant regions, including cortical, limbic and arousalcenters (e.g., pontomesencephalic tegmentum, amygdala, basal forebrain,somatosensory cortex), that can be non-invasively stimulated to modulateascending activity along the central auditory pathways and suppresstinnitus.

FIG. 2. Post-stimulus time histograms of multi-unit spike activityrecorded on the same ICC site in response to an 8 kHz pure tone (bar; 30dB SPL). Spontaneous and acoustic-driven spiking activity is shown.First arrow shows how the activity changes after repeated ICX electricalstimulation (100 μA, 205 μs pulse) synchronized with 8 kHz pure tonestimulation (30 dB SPL). Second arrow shows recovery of response backtowards the initial response simply by waiting (e.g., minutes to hours),supporting that the brain maintains some fixed reference representationthat automatically drives the system back to a normal state.

FIG. 3. FIG. 3 depicts an example from one noise-damaged animal in whichusing the synchronized stimulation paradigm reduced the elevatedspontaneous spiking activity back to a normal range without altering theacoustic-driven activity. Several neurons sensitive to 4-8 kHz showelevated spontaneous activity compared to those outside that frequencyrange (mean and S.D., n=39) consistent with previous studies. “Neuron”refers to multi-unit activity recorded on a site.

FIG. 4. Data showing spiking activity recorded in ICX for an electricalpulse (205 μs phase) of the neck (450 μA) The shoulder was stimulated 2,4, or 6 ms before the neck (rows; 400 μA) and the activity across 3sites 100 μm apart is shown (columns). Arrow points to largeststimulus-evoked response for the −6 ms delay that becomes weaker for theother delays. Stimulation across body sites elicits activity in ICX thatdepends on recording location and inter-site delay.

FIG. 5. Data of spiking activity recorded on 2 different sites in ICC(300 μm apart) in response to acoustic stimulation (5 kHz tone, 60 dBSPL, bar=duration) before and after our synchronized body-soundstimulation paradigm for several minutes (repeated 2/s). Ch7 showssignificant changes in the temporal pattern of activity. Ch4 showsslight changes in the response onset but significant suppression ofspontaneous activity, suggesting elevated activity caused by tinnituscould be suppressed using this method.

FIG. 6. FIG. 6 depicts aspects of the methods described herein fortreating a patient having tinnitus with synchronized stimulation, whichsynchronized stimulation includes auditory stimulation delivered usingheadphones and non-auditory stimulation caused by transcutaneouselectrical nerve stimulation (TENS), which synchronized stimulation isdelivered by a device having a user interface.

DETAILED DESCRIPTION

Certain embodiments of the invention provide a method for treating apatient having a neurological disorder or deficit, comprising deliveringto the patient at least one synchronized stimulation to the brain,wherein the synchronized stimulation comprises stimulation from at leastone auditory pathway and stimulation from at least one non-auditorypathway.

Certain embodiments of the invention provide a method for treatingtinnitus in a patient in need of such treatment, comprising deliveringto the patient at least one synchronized stimulation to the brainwherein the synchronized stimulation comprises stimulation from at leasttwo non-auditory pathways.

Certain embodiments of the invention provide a method for treatingtinnitus in a patient in need of such treatment, comprising deliveringto the patient at least one synchronized stimulation to the brain,wherein the synchronized stimulation comprises stimulation from at leastone auditory pathway and stimulation from at least one non-auditorypathway.

Certain embodiments of the invention provide a method for treating apatient having a neurological disorder or deficit (e.g., a phantomprecept such as tinnitus or phantom limb pain), comprising delivering tothe patient at least one synchronized stimulation to the brain, whereinthe synchronized stimulation comprises stimulation from at least oneauditory pathway and stimulation that induces anxiety and/or stress inthe patient.

Certain embodiments of the invention provide a method for treating apatient having a neurological disorder or deficit (e.g., a phantomprecept such as tinnitus or phantom limb pain), comprising delivering tothe patient at least one synchronized stimulation to the brain, whereinthe synchronized stimulation comprises stimulation from at least onenon-auditory pathway and stimulation that induces anxiety and/or stressin the patient.

In certain embodiments, the neurological disorder or deficit is aphantom percept.

In certain embodiments, the phantom percept is tinnitus or a phantomlimb percept.

In certain embodiments, the phantom percept is tinnitus.

In certain embodiments, the phantom percept is phantom limb pain.

In certain embodiments, the neurological disorder or deficit is pain,body tremors, motor deficits, hyperacusis, or a psychological or mentaldisorder.

In certain embodiments, the psychological or mental disorder isobsessive compulsive disorder, depression, stress, a memory or learningdisability, a speech impediment, a visual hallucination, or an auditoryhallucination.

In certain embodiments, the synchronized stimulation involves a stimuluspattern lasting up to about 1 second for each activated pathway.

In certain embodiments, the synchronized stimulation involves a stimuluspattern lasting between 0.01 to 100 ms for each activated pathway

In certain embodiments, a specifically determined time between eachactivated pathway ranges between 0-1000 ms.

In certain embodiments, in the at least one non-auditory pathway is asensory pathway from the patient's head, face, ear, eye, nose, mouth,lip, tongue, tooth, neck, body, limb, genital areas, buttocks/anusregions, hand, finger, foot, or toe.

In certain embodiments, the synchronized stimulation comprisesstimulation of multiple non-auditory pathways of up to 10 sites acrossthe patient's head, face, ear, eye, nose, mouth, lip, tongue, tooth,neck, body, limb, genital areas, buttocks/anus regions, hand, finger,foot, or toe.

In certain embodiments, the synchronized stimulation comprisesstimulation of multiple non-auditory pathways of more than 10 sitesacross the patient's head, face, ear, eye, nose, mouth, lip, tongue,tooth, neck, body, limb, genital areas, buttocks/anus regions, hand,finger, foot, or toe.

In certain embodiments, the synchronized stimulation comprisesstimulation of multiple non-auditory pathways of more than 100 sites(e.g., from 101-200, 201-300, 301-400, 401-500, 501-600, 601-700,701-800, 801-900, 901-1000) across the patient's head, face, ear, eye,nose, mouth, lip, tongue, tooth, neck, body, limb, genital areas,buttocks/anus regions, hand, finger, foot, or toe.

In certain embodiments, the synchronized stimulation comprisesstimulation of multiple non-auditory pathways of more than 1000 sitesacross the patient's head, face, ear, eye, nose, mouth, lip, tongue,tooth, neck, body, limb, genital areas, buttocks/anus regions, hand,finger, foot, or toe.

In certain embodiments, a single synchronized stimulation is delivered.

In certain embodiments, multiple discrete synchronized stimulations aredelivered every 100 to 10000 ms apart (e.g., 100, 200, 300, 400, 500,750, 1000, 2500, 5000, 7500, or 10000 ms apart) for a total durationranging from 1 s to 1 hour that can be repeated as many times as neededfor treatment.

In certain embodiments, the stimulation from the at least onenon-auditory pathway is evoked by non-invasive stimulation.

In certain embodiments, the stimulation from the at least onenon-auditory pathway is evoked by transcutaneous electrical stimulation.

In certain embodiments, the stimulation from the at least onenon-auditory pathway is evoked by vibration, pressure, heat, optics,magnetic, ultrasound, taste or scent stimulation.

In certain embodiments, the stimulation from the at least onenon-auditory pathway is evoked by a single pulse or pulse train.

Visual flashes, images, pressure patterns, complex cognitive or motortasks, complex or pleasurable smells and tastes, unexpected andtransient stimuli, startle stimuli, temperature changing stimuli,complex vibrations may also be used as the stimulation.

In certain embodiments, the stimulation from the at least onenon-auditory pathway is evoked by a sinusoid.

In certain embodiments, the stimulation from the at least onenon-auditory pathway is evoked by a constant or complex shape.

In certain embodiments, the stimulation from the at least onenon-auditory pathway is evoked by subcutaneous electrical stimulation.

In certain embodiments, the stimulation from the at least onenon-auditory pathway is evoked by epidural, surface, or penetratingcortical stimulation.

In certain embodiments, the stimulation from the at least onenon-auditory pathway is evoked by a single pulse or pulse train.

In certain embodiments, the stimulation from the at least onenon-auditory pathway is evoked by a sinusoid.

In certain embodiments, the stimulation from the at least onenon-auditory pathway is evoked by a constant or complex shape.

In certain embodiments, the synchronized stimulation from the at leastone auditory pathway is evoked by sound.

In certain embodiments, the synchronized stimulation from the at leastone auditory pathway is evoked by vibration of the head, outer or middleear structures, cochlea, or head fluids.

In certain embodiments, the synchronized stimulation from the at leastone auditory pathway is evoked by one or more pure tone frequencies.

In certain embodiments, the synchronized stimulation from the at leastone auditory pathway is evoked by bandwidth filtered sinusoids or noise.

In certain embodiments, the synchronized stimulation from the at leastone auditory pathway is evoked by a complex waveform.

In certain embodiments, the synchronized stimulation from the at leastone auditory pathway is evoked by electrical stimulation of the auditorynerve.

In certain embodiments, the synchronized stimulation from the at leastone auditory pathway is evoked by optical, magnetic, or ultrasoundstimulation of the auditory nerve.

In certain embodiments, the synchronized stimulation from the at leastone auditory pathway is evoked by electrical stimulation within thebrain, including the cochlear nucleus, inferior colliculus, medialgeniculate, cortex.

In certain embodiments, the synchronized stimulation from the at leastone auditory pathway is evoked by optical, magnetic, or ultrasoundstimulation within the brain, including the cochlear nucleus, inferiorcolliculus, medial geniculate, cortex.

In certain embodiments, the synchronized stimulation from the at leastone auditory pathway is evoked by non-invasive electrical, magnetic, orultrasound cortical stimulation.

In certain embodiments, the synchronized stimulation from the at leastone auditory pathway is evoked by epidural, surface, or penetratingcortical stimulation.

In certain embodiments, the stimulation from the at least one auditorypathway is evoked by a single pulse or pulse train.

In certain embodiments, the stimulation from the at least one auditorypathway is evoked by a sinusoid.

In certain embodiments, the stimulation from the at least one auditorypathway is evoked by a constant or complex shape.

In certain embodiments, the method may further comprise delivering astimulus that induces anxiety and/or stress in the patient.

In certain embodiments, the stimulus that induces anxiety and/or stressis a specifically-delivered unexpected stimulus, such as anuncomfortable stimulus.

In certain embodiments, the stimulus that induces anxiety and/or stressis a specifically-delivered stimulus that induces a startle response.

As described herein, a midbrain region (inferior colliculus) as well asa brainstem region (reticular activating nuclei) has been discoveredthat can be stimulated, e.g., directly stimulated with electricalcurrent, combined with acoustic stimulation to shift the firing patternsof neurons within the central auditory system. This stimulation is ableto shut off or alter neural changes resembling the types of activityobserved in tinnitus animals. As described herein, it may be possible to‘turn off’ the abnormal neural changes observed in tinnitus, thusproviding a method for suppressing tinnitus in a large patientpopulation. Although it is possible to directly stimulate these midbrainor brainstem regions with surface and penetrating arrays implanted intothe head in severe tinnitus patients, a non-invasive method to achievethis effect may also be used to treat a larger patient population. Thesemidbrain and brainstem regions are multi-modal brain centers thatreceive projections from various regions all over the head and body(e.g., skin surface and muscles coming from the face, eyes, head, pinna,neck, mouth, tongue, lips, upper extremities, upper spinal cord, genitalareas, and other regions not yet identified) as well as projections fromthe cortex. The genital areas have significant projections to pleasure,limbic, and arousal brain centers that can be activated non-invasivelyand combined with acoustic stimulation to shift activity in the auditorypathways to suppress tinnitus. In certain embodiments, the patient(e.g., a human male or human female) receiving the stimulation to thegenital area is sexually aroused, and in certain embodiments the patientis not sexually aroused. The midbrain region is involved in multi-modalprocessing (e.g., audio-visual orienting reflex). The brainstem regionis involved in arousal and sleep-wake cycles. It has been discoveredthat it is possible to non-invasively (e.g., transcutaneously) stimulatethese different regions and projection pathways using surface electrodeson the skin. Other options for stimulation include using heat,ultrasound, optics, magnetic, mechanical, etc., instead of electricalcurrent. A newly discovered embodiment is to transiently stimulate thesedifferent regions simultaneously, or with some interval, so that theinputs reach these different brainstem and/or midbrain centers at thesame time to cause a synchronized “shock” pattern that can then modifyneurons, e.g., tinnitus-affected neurons. Activation of these differentpathways can also activate other brain targets involved with plasticityand reinforcement that can modify neurons, e.g., tinnitus-affectedneurons.

Stimulation of the genital area will be able to access thearousal/limbic inputs that can reinforce the neural changes. The tongue,face, foot sole, finger pads, and spinal back area have more sensitivityand smaller receptive fields, so those areas may provide greater abilityfor coordinated and thus targeted brain activation. The shoulder, neck,and ear are involved with the orienting reflex response and are moretightly coupled with the auditory system and could be effective inmodulating auditory activity.

In certain embodiments, at least one of the following brain areas is the‘target’ brain area for delivering the synchronized stimulation. Certainauditory brain areas include the cochlear nucleus, the laterallemniscus, the inferior colliculus, the medial geniculate nucleus andthe auditory cortex. Certain non-auditory brain areas includethe-reticular activating nuclei (e.g., the pontomesencephalictegmentum), the limbic nuclei (e.g., the amygdala, hippocampus,cingulate gyms, nucleus accumbens), the basal forebrain, the cholinergicsystem and the noradrenergic system. Certain of these areas aredescribed in FIG. 1.

The number of areas stimulated can, in certain embodiments, be up to 10,from 10-100 or from 100-1000, and in certain embodiments, more than1000. This will effectively stimulate numerous sites across differentsurface regions in a temporally coordinated pattern. This providescoordinated timing of transient stimuli between multiple sites that areeffectively synchronized with acoustic stimulation to provide thesynchronized stimulation. Direct nerve or brain stimulation may be usedin certain embodiments because, e.g., there are patients implanted inthese regions for hearing restoration who also have tinnitus. It wouldbe possible to directly stimulate these patient's brains, combined withstimulation of the other auditory and non-auditory sensory pathways.

While not intended to be a limitation of the present invention, it isbelieved that the brain maintains memory of how things used to be eventhough the brain may adapt and change to code for new features. In otherwords, there are fixed “original” representations in the brain that arecontinuously maintained to keep some order in the brain and newrepresentations (whether normal plasticity to learning or abnormal dueto disease states, such as tinnitus) that co-exist simultaneously. Thebrain can then switch between these states quite easily and rapidly. Inthis context, the auditory system is described herein for the first timeas a fixed/plastic organization with at least one neural switch. Assuch, the concept and method to non-invasively activate this neuralswitch to return the abnormal brain back to a normal state to suppresstinnitus is described herein.

Certain embodiments provide a non-invasive method to suppress tinnitusby using surface stimulation. If necessary, electrodes can be implanteddirectly onto or into nerves with minimally invasive techniques. Formore severe cases, brain surgery can also be considered to implantsurface and/or penetrating electrode arrays to directly stimulate thedifferent midbrain and brainstem regions involved with this neuralswitch. The fact that other brain regions (e.g., thalamus, cortex,limbic nuclei, basal forebrain) are interconnected with these brainstemand midbrain regions and contribute to the tinnitus effect, othermulti-modal projection pathways can be stimulated non-invasively orinvasively.

There have been attempts at presenting acoustic stimulation to eitherrestore some of the hearing loss driving the tinnitus or to directlymask the tinnitus. However, simply using acoustic stimulation does notappear to be powerful enough to fully restore lost frequencyrepresentations. As described herein, an important difference betweenpreviously-proposed treatments and what is proposed herein is that it isnot necessarily an object of the invention to neuromodulate and retrainthe brain back to normal. What is proposed herein is a new concept thatthe brain has its original state hidden under an abnormal diseasedrepresentation. The methods provided herein “shock” the brain to switchback to its original state. This is not trying to retrain the brain, butinduce a “shock” to reset it back. Although it is tempting to relatethis to defibrillation, there are some distinct differences.Fibrillation is where the heart goes from being normal to abnormalfiring, and then the heart is shocked to depolarize all the neurons atonce with a slight pause to then go back to its normal state. Fortinnitus, there are situations where there can be a sudden shift of theneurons from a normal to abnormal state but usually it involves somechanges that occur over time that then reorganize the brain to representthis abnormal state. So there is a new representation of sound coding inwhich both the old and new co-exist at the same time, but the old stateis hidden. The idea is then to switch the brain back to the normalstate. While not necessarily an object of the invention, it is proposedthat the normal brain actually does this in learning new sound codingstrategies but also happens for abnormal diseased states. Treatment canbe achieved, e.g., with a single or several highly synchronous stimuli(e.g., shocks) combined with acoustic stimulation. This paradigm can berepeated periodically over hours or days or weeks, as needed. In oneaspect, electrodes may be permanently implanted under the skin (e.g.,wireless micro-electrodes) for repeated presentation as needed by thepatient.

Even if, for the sake of argument, others may have proposed combiningacoustic stimulation with vagal nerve or tongue stimulation, and othergroups for the sake of argument may have proposed stimulatingnon-auditory regions, none has yet proposed to stimulate these regionsto induce a highly synchronized “shock” in the brain. As such, theacoustic stimulation is combined with the electrical stimulation so thatthe projection pathways to the neural switch regions are synchronouslyactivated, whether using electrical, acoustic, or any other form ofactivation. For example, the cochlea or auditory nerve could bestimulated for those with significant hearing loss or even stimulate thenerve non-invasively or with minimal invasiveness even in patients withhearing. In certain embodiments, the auditory and non-auditory cortexare stimulated (invasively or non-invasively) in combination withanother pathway to induce a synchronous shock.

Synchronized stimulation refers to transient stimulation (e.g., 0.01-100ms) of at least two different pathways in a specific time relative toeach other (e.g., 0-1000 ms). The timing is designed and optimized toinduce effective activation of one or more specific brain regions toaffect the tinnitus percept while other brain regions are noteffectively activated because the timing is not optimized for thoseregions. In turn, this allows for targeted brain activation withouthaving to actually implant and stimulate invasively within thoseregions. Effectively refers to the ability to alter the tinnitus perceptto a subjectively improved state (e.g., not only suppression but alsoany alteration that could still improve the subjective tinnitus state).

In certain embodiments, the auditory and non-auditory cortex will bestimulated (invasively or non-invasively) in combination withsynchronized stimulation of the other pathways described herein toinduce a “shock” within the brain. Cortical stimulation is one possiblepathway.

In some embodiments, the synchronized stimulation does not comprisevagal stimulation.

In some embodiments, the synchronized stimulation does not comprisestimulation of the tongue.

Previous Tinnitus Treatments

Unfortunately, there is no cure or reliable treatment for tinnitus.Various drug therapies, electrical and mechanical stimulation methods,psychotherapy techniques, and sound treatments have been attempted butwith mixed results. Several types of drugs and substances (e.g.,anti-anxiety: Xanax; anti-depressants: nortriptyline; vitamins: zinc;herbs: Gingko biloba) have alleviated the tinnitus percept in someindividuals, but this benefit is likely due to a reduction in thepsychological feelings towards the tinnitus or a placebo effect. It hasnot been clear which neural mechanisms should be targeted to suppresstinnitus. Similarly, psychotherapy treatments have focused on improvingthe patient's ability to cope with the tinnitus and have resulted invariable outcomes. Acoustic therapy has attempted to mask the actualphantom sound percept. However, this requires continuous presentation ofanother sound source and upon termination, the tinnitus percept returns.

More recently and based on an increased understanding of the causes oftinnitus (described herein) and its link to abnormal changes within thecentral auditory system, creative acoustic and electrical stimulationmethods are being investigated to reverse these abnormal patterns backto normal. Tinnitus is currently viewed as a brain phenomenon in whichdifferent types of causes all lead to some reorganization of the centralauditory system to elicit the phantom percept. The most common type oftinnitus is associated with noise-induced hearing loss. The auditorysystem consists of neurons that are spatially ordered based on theirsensitivity to different frequencies (i.e., tonotopic organization)within each nucleus from the cochlea up to the auditory cortex (FIG. 1).High levels of noise will damage neurons in the cochlea coding forspecific frequency components, eliminating excitatory and inhibitoryinputs into more central regions representing those frequencies. Neuronscoding for those lost frequencies also become more sensitive to otherfrequencies. The overall imbalance of inputs initiates a cascade ofneural changes throughout the auditory system, such as tonotopicreorganization (e.g., expanded frequency regions), increased firing,over-synchrony across neurons, and abnormal bursting patterns. Thesechanges can be most prevalent in neurons coding for the lostfrequencies, which can match the range of frequencies associated withthe tinnitus percept. The second most common type of tinnitus isassociated with head and neck injuries in which damage to non-auditoryneural pathways, which project to auditory neurons, causes an imbalancein the excitatory and inhibitory networks within the central auditorysystem and leads to a phantom percept. Tinnitus can also develop throughdysfunction of non-auditory networks associated with limbic andcognitive centers that feed back into and alter the auditory system.

Considering the neural changes associated with tinnitus, several methodshave attempted to restore the lost input driving those changes orneuromodulate the tinnitus-affected neurons to induce sufficientplasticity that would suppress the phantom percept. For those withsufficient hearing, headphones or hearing aids attempt to amplify andfill in missing acoustic information to drive the brain back to normalthrough plasticity. Rather than fill in the missing acousticinformation, other techniques have attempted to modulate and fix thetinnitus-affected neurons through neural stimulation, such as corticalactivation using transcranial magnetic stimulation or epidural surfacestimulation. Cortical stimulation modulates neurons within the auditorycortex and activates the massive descending network to subcorticalneurons that are all contributing to the tinnitus percept. There arealso many non-auditory pathways (e.g., from the head, face, body, limbs)that project onto cortical and subcortical auditory neurons. Some ofthese pathways have been activated with transcutaneous electricalstimulation or acupuncture to modulate neurons in multi-modal centersthat can then alter tinnitus-affected neurons. However, these treatmentshave been unreliable.

Rationale

All of the plasticity-based methods described above have provided mixedresults in which some patients may seem to experience a reduction oftheir tinnitus while others experience no changes or even an increase intheir tinnitus. One major hurdle to these methods is that there arenumerous types of tinnitus that have a wide range of causes and timecourses. Each tinnitus brain may have experienced a different sequenceof neural changes and have different capabilities for enablingsufficient plasticity to the different treatments. Furthermore, thesedifferent methods are only able to crudely or indirectly activate thenecessary auditory pathways to restore back the normal state, whichitself consists of an intricate organization. For example, it is unclearhow stimulation of the tongue would indirectly transmit features to theauditory brain that are sufficient to restore the intricate soundfeatures that have been lost through the natural hearing pathway. Itwould seem that stimulation of the tongue could modify some auditoryneurons through plasticity but not in such a precise way to restore backthe detailed original organization. In terms of neuromodulation, it isunclear how crude surface cortical stimulation would be able to activateclusters of cortical neurons and descending pathways in a precise mannerto sufficiently drive different central auditory neurons located inspecific regions back to normal.

Rather than presume that these various stimulation treatments were ableto somehow drive precise plasticity to restore normal auditory function,the current fundamental understanding of how the brain maintains andadapts its sensory representation to relevant or persistent stimuliunder normal and pathological conditions was questioned, as describedherein. It was questioned whether the brain maintains a continuousrepresentation of its original state, at least for fundamental features,that is simply suppressed during the development of new learned orpathological states. In this way, the original representation could berecalled if the appropriate neurons were activated, mimicking a “neuralswitch” rather than a typical plasticity mechanism as proposed for theseprevious treatments. During tinnitus, the driving source may bepreventing the neurons from returning to their original state, but withappropriate activation of certain neural pathways, the brain may then beable to switch back to normal.

No studies have investigated or demonstrated dual fixed-plasticrepresentations for tonotopy or other neural firing properties, such asspontaneous rates and synchrony, within the central auditory system. Itwas predicted that tonotopy would exhibit this dual state behaviorconsidering that every nuclei along the main ascending auditory systemhas a frequency organization (i.e., the most fundamental feature of theauditory system; FIG. 1).

As described herein, there are pieces of evidence that collectively forma reasonable argument for the existence of fixed-plastic states fordifferent features within the auditory brain. More importantly, if aneural switch for tinnitus-related states (e.g., for tonotopy andspontaneous firing and synchrony across neurons) can be identified andactivated through non-invasive stimulation methods to reset alteredneurons back to normal, this would have a significant clinical impactfor the large number of tinnitus patients. With these thoughts andjustifications in mind, a search for this neural switch was undertaken.Since then, the important role of the descending projections from theprimary auditory cortex (A1) to IC in enabling physiological andbehavioral plasticity for sound localization and frequency tuning hasbeen investigated. Through the massive ascending and descendinginterconnections between all the auditory nuclei (FIG. 1), neuralchanges within IC would then be reflected throughout the centralauditory system, including the auditory cortex. Unfortunately, therewere no studies describing the detailed anatomical or functional spatialorganization of projections from A1 to IC to understand how plasticitycould be enabled through this pathway. Thus, experiments were conductedto anatomically and functionally map these projections by electricallystimulating throughout A1 and recording the effects in differentlocations across IC using multi-site electrode arrays. It has beendemonstrated that A1 projects to the central region of IC (ICC) in aprecise tonotopic pattern (e.g., a 10 kHz sensitive A1 neuron mainlyprojects to and excites a 10 kHz ICC neuron). There appears to bedistinct locations within A1 that project to distinct locations withinICC representing parallel descending pathways. It was also observed thatA1 has a large and diffuse projection pattern throughout the outer IC(ICX), which further projects to ICC (FIG. 1). Based on these findings,it was hypothesized that the direct A1-to-ICC projections sculpt thefine plastic changes within ICC that is reinforced by broad input fromthe A1-to-ICX pathway. In other words, ICX serves some gating functionto enable plasticity within ICC but can also prevent or reset any newchanges. Thus, it appeared to be a potential region for the neuralswitch.

Therefore, the next step was to directly stimulate ICX and attempt toidentify a neural switch mechanism by measuring the activation effectswithin ICC. After much research, a way to switch neural states withinICC was discovered by electrically stimulating the ICX combined withacoustic stimulation in a precisely timed manner. FIG. 2 shows howspiking activity within the ICC can be altered or suppressed after thesynchronized ICX-acoustic stimulation. The ICX was stimulated with anelectrical pulse and the acoustic stimulus was a pure tone. The timingwas synchronized such that the activity induced by each modality arrivedat the ICC site at a similar time, thus achieving synchronizedactivation. After repeated activation with the synchronized paradigm,the ICC activity was altered (first arrow). However, without providingany additional input, the system began to return back to its originalresponse (second arrow) supporting that the brain maintains a referencestate that drives the system back to normal. The brain could berepeatedly altered with the synchronized stimulation (last arrow) andthen allowed to recover after a waiting period. It is possible thatappropriate brain activation could speed up the recovery period.

In FIG. 2, the brain was altered to artificial synchronized stimulation(e.g., for 10 minutes) and then began recovering back to its normalstate. In a pathological brain state, the normal state is somehow unableto drive the neurons to its original state. The question arose as towhether the synchronized stimulation paradigm could alter and reversebrain activity that experienced long-term changes associated with apathological state. It has been shown that presenting a loud (>124 dBSPL) pure tone for over one hour can induce a severe hearing loss at andslightly above that pure tone frequency. These animals then develophyperactivity across many neurons sensitive to those compromisedfrequencies within multiple auditory nuclei, including the ICC, whichleads to a tinnitus that matches those frequencies. To investigate thisfurther, hearing loss was induced in three animals with a 4 kHz puretone presented at −120 dB SPL for one hour and they developed thehighest ICC thresholds between approximately 4 to 8 kHz. Elevatedspontaneous firing rates were observed in several ICC neurons tuned tothose frequencies. Encouragingly, the elevated spontaneous activity wassuppressed into a normal range using the synchronized paradigm describedherein (FIG. 3). What was even more surprising was that it was possibleto suppress the spontaneous activity, presumably linked to tinnitus,without affecting the acoustic-driven pattern. This is important toensure suppression of tinnitus without altering normal auditory codingfunction. Overall, these initial results demonstrate that thesynchronized stimulation paradigm can suppress elevated firing patterns,similar to those observed in tinnitus animals, back to a normal range.

Additional research focuses on performing neurophysiology and perceptualexperiments in guinea pigs to refine the therapy and confirm itseffectiveness and safety in suppressing tinnitus. In the early stages ofthe project, plasticity experiments will be performed to demonstratethat a fixed-plastic state exists for tinnitus-related features and thatthe brain can switch states through this ICX neural switch. Additionalswitching mechanisms within the brainstem and thalamus (FIG. 1) willalso be examined. Both of these regions exhibit neural changes totinnitus and receive descending projections from auditory cortex thatare involved with plasticity. Thus, stimulation of the outer portions ofthese regions (e.g., CNX and MGX) involved with descending plasticitycould also serve to switch activity within their main ascending pathways(e.g., CNV and MGV). There are also non-auditory regions that project tothe auditory system, including the reticular activating system, thelimbic nuclei, and basal forebrain, that can also be stimulated toswitch states with the auditory system linked to tinnitus.

The ability to stimulate the reticular activating system (i.e.,pontomesencephalic tegmentum, PPT) to be able to shift coding propertieswithin the ICC has been demonstrated. Once this neural switch mechanismis confirmed across these multiple brain regions, then their ability toswitch states in hearing loss and different tinnitus animals will bedetermined. Tinnitus can be induced by exposing animals to very loudsounds for a certain period of time that damages their peripheral systemand causes central plastic reorganization leading to the phantompercept. Tinnitus can also be induced with ototoxic drugs (e.g.,salicylate, such as aspirin) administered to the animal. Both of thesemethods yield several conditions resembling those experienced in humanswho have developed tinnitus. The goal will be to demonstrate thatstimulation of different neural switch regions, either individually orcollectively, reverses the neural changes caused by tinnitus to suppressthe phantom percept regardless of its cause or time course. Neuralchanges can be assessed using multi-site extracellular recordings acrossmultiple brain regions (e.g., >100 simultaneous sites) and perceptualeffects using the startle response test, which is a sound reflexparadigm described later.

An important component of this project is ultimately to activate theneural switch regions non-invasively. One embodiment includesnon-invasively activating ICX, CNX, MGX, reticular activating nuclei,limbic nuclei, and/or other neural switch centers using multi-modaltranscutaneous stimulation. Direct electrical stimulation of the braininduces a highly synchronous shock that simultaneously activates cellbodies and passing fibers within a specific region, which is what wasinduced during ICX stimulation to achieve the effects in FIGS. 2 and 3.Fortunately, ICX is involved with multi-modal processing (e.g.,audio-visual orienting reflex) and receives converging inputs from allover the head, face, ears, eyes, mouth, tongue, neck, body, and limbs(FIG. 1). The trigeminal nerve, dorsal root of spinal nerve, opticnerve, auditory cortex, and somatosensory cortex all project to ICX.Similarly, many of these pathways have shown to project to the CNX, MGX,reticular activating system, and other potential neural switch centers(FIG. 1). In certain embodiments, multiple surface electrodes arepositioned over the head, face, ears, eye regions, mouth, tongue, neck,body, genital areas, limbs, foot sole, and digits (e.g., up to 10, 20,100 or 1000). These electrodes can then be stimulated simultaneously orwith specifically-timed delays to activate as many of the non-auditorypathways and induce a highly synchronous shock in those neural switchregions. Non-invasive cortical stimulation (e.g., surface ortranscranial magnetic stimulation) to activate the descending auditoryand somatosensory cortex projections or shining light into the eye toactivate the optic nerve projections, in addition to transcutaneousstimulation of the other regions, are possible. Other forms ofstimulation may be cognitive tasks, motor task/movement, flashes,images, complex pressure patterns, temperature changes, scents, tastes,etc. To further drive the neural switch, this electrical shock iscombined with an acoustic stimulus, e.g., that can be presented viaheadphones. In the animals, subcutaneous needles and even direct nervestimulation can be used to identify optimal locations as well asappropriate timing across sites. After assessing the safety of thetreatment over longer periods of time (i.e., safe current levels toavoid tissue damage and seizures, neural adaptation and reliability overtime, specificity to cause only auditory state changes), these findingscan be extrapolated to human patients.

In animals, the ability to actually activate and alter coding propertiesin the auditory system through surface body synchronized stimulation isdescribed. FIG. 4 shows an example of stimulating a local region of theneck and left shoulder with electrical biphasic pulses through needleelectrodes that were precisely timed 6 ms apart to elicit synchronizedactivity in ICX that was weaker or absent with a different delay (e.g.,2 or 4 ms). Stimulation of each site individually caused activationacross different ICX regions. It was also possible to alter spontaneousand sound-driven spiking activity within ICC after the synchronizedactivation paradigm (FIG. 5). These results provide consistent evidencefor the ability to alter coding properties within the auditory system inresponse to coordinated stimulation across the body and ear input, andits potential ability to suppress tinnitus.

Multi-Modal Non-Invasive Neural Shock Therapy

In the past decade, the brain stimulation field has grown rapidly withmore than 75,000 patients implanted with a penetrating or surface arraywithin various brain regions for treating numerous neurologicalconditions (e.g., tremors, pain, tinnitus). However, these brainstimulation approaches can only be used in a limited patient populationdue to their invasiveness, need for advanced surgical resources,time-consuming fitting by trained personnel, and high cost. Furthermore,it is not possible to re-insert the array into numerous locations toidentify optimal regions for stimulation to deal with patientvariability. There have been a few noninvasive attempts at stimulatingthe brain to address some of the issues above, including transcranialmagnetic stimulation (TMS) and transcranial direct current stimulation(tDCS). For TMS, a magnetic coil is positioned over the head to inducecurrent within the brain. tDCS applies a constant current through theskull through surface electrodes to alter the depolarization state ofneurons. Both TMS and tDCS activate a large volume of mostly corticalneurons that is unavoidable when noninvasively activating through theskull. The comparison between TMS or tDCS versus direct brainstimulation highlights the critical trade-off between noninvasivenessversus specificity that has not yet been resolved.

An innovation described herein is a low-cost treatment that achievesboth noninvasiveness and specificity. It takes advantage of the denseand coordinated interconnectivity across sensory, motor, cognitive, andlimbic centers. One center may exhibit abnormal activity driving theneurological disorder. The goal of the treatment is to activate specificpathways related to the other modalities and with appropriate timing tothen modulate and ‘fix’ the abnormal region. This assumes that thesedifferent pathways can interact and induce plasticity across centers,which is expected considering the necessity for precise coordination andreinforcement among these modalities during daily function and survival.Each neuron of the brain receives inputs from many different neurons andcan be affected by multiple sensory, motor, cognitive, and limbicmodalities. Therefore, there is more than one means to affect a givenneuron, and thus activating as many of those ways as possible and in asynchronized pattern would elicit artificial and strong activation ofthat neuron to alter its state. Repetitive activation of that neuron orgroups of neurons would then lead to long-term plasticity, shifting itaway from the abnormal state and suppressing the neurological condition(e.g., tinnitus). The treatment may need to be applied periodicallysince it may not cure the neurological condition but rather eliminatethe debilitating symptoms.

One embodiment of this approach is for tinnitus suppression that appliescoordinated activation of auditory and somatosensory pathways. Atopographic organization of neurons within the auditory midbrain wasdiscovered that can be differentially activated by different bodylocations in guinea pig. In other words, stimulation of differentcombinations of body locations with appropriate delays appears toactivate different and specific neurons across the auditory midbrain,which in turn projects to other regions throughout the auditory systemthrough ascending and descending pathways. Thus, a treatment describedherein enables localized auditory activation without having to actuallyimplant an electrode into the brain. Customized acoustic stimuli canthen be used to reinforce or interact with those activated midbrainneurons that in turn would modulate and potentially induce plasticityacross the auditory system. Other embodiments of this treatment wouldincorporate other reinforcement inputs, such as visual cues,cognitive/emotional effects, reward/pleasurable stimuli, and slightlypainful stimuli that could all contribute to synchronization andenhanced plasticity within the brain.

This multi-modal synchronization therapy is not limited to treatingtinnitus. For example, it could be used to treat phantom limb pain.Specific parts of the phantom limb or other somatosensory pathways couldbe stimulated (e.g., using current, pressure, or temperature stimuli) toactivate neurons linked to or interacting with the pain that are thenaltered and reinforced by activation of the other modalities. Forcognitive or emotional disorders, the activation process may be morecomplex but this approach could still be effective. For example, if thepatient has a memory or learning issue, cognitive tasks that are alreadyused in the field can be implemented. What is innovative about theapproach described herein is the combination of these standard taskswith activation of other modalities. It is possible to providecoordinated body stimulation or even slightly painful but comfortableelectrical shocks on the body in combination with a task. Not only couldthis induce synchronized activation of target brain regions, but itwould also lead to elevated states of anxiety or excitement, naturallyreleasing neurotransmitters that could enhance plasticity andreinforcement to the task. This approach may be combined with stimuli toinduce anxiety and increased attention, which in turn could enhance theplasticity to drive the neural changes back to normal. Other types ofneurological disorders or deficits that are associated with abnormal andreversible neural patterns could also benefit from this multi-modalsynchronization and noninvasive approach. This includes pain, bodytremors, motor deficits, hyperacusis, and even psychological and mentaldisorders (e.g., obsessive compulsive disorder, depression, stress,memory or learning disability, speech impediment, and visual/auditoryhallucinations).

There are numerous studies showing that activation of the limbic systemas well as stimulation of the nucleus basalis, locus coeruleus, vagusnerve, and pedunculopontine nucleus can enhance plasticity within thebrain, including the auditory system. However, direct stimulation ofthese regions within the brain requires invasive surgery. An alternativeto this approach is to noninvasively and naturally activate the brain torelease similar types of neuromodulators (e.g., acetylcholine,epinephrine, norepinephrine, serotonin, and dopamine) that can enhanceplasticity. Certain embodiments of the treatments described herein arebased on providing an unexpected and slightly painful stimulus that issynchronized with activation of other modalities. This unexpectednesswill create anxiety and increased attention to the different stimuli,which in turn would naturally release neuromodulators required for brainplasticity. This release of neuromodulators can occur by activation ofpathways through the pedunculopontine nucleus and amygdala that alsointeract with the nucleus basalis, locus coeruleus, and other limbicregions associated with attention, awareness, and emotion.

Experiments have been performed by electrically stimulating thepedunculopontine nucleus combined with acoustic stimuli and have shownthe ability to alter firing patterns within the inferior colliculus. Notonly is it possible to suppress or enhance acoustic-driven andspontaneous firing activity, it is also possible to shift the frequencytuning sensitivity of the neurons. These changes can last for tens ofminutes to hours. These types of changes should enable modulation ofabnormal patterns associated with tinnitus. As described herein, theauditory cortex has been stimulated in combination with acousticstimulation and altered coding properties within the inferiorcolliculus, which in turn projects throughout the auditory system viaascending and descending pathways. Therefore, activation of limbic anddescending pathways can contribute to neural plasticity throughout theauditory system.

For future experiments, the effects of unpredictability-based stress andanxiety response therapy (USAR therapy) in awake and behaving animals,including those with tinnitus, will be conducted. For USAR therapy, aslightly painful shock to the animals will be delivered while recordingin the pedunculopontine nucleus, nucleus basalis, locus coeruleus, andother limbic centers to demonstrate that heightened anxiety andattention can alter firing patterns in these regions. However, it willbe important to then combine this unexpected shock stimulus withacoustic stimuli, somatosensory stimuli, and activation of othermodalities to demonstrate that firing patterns can actually be modifiedwithin the inferior colliculus and throughout the auditory system. Todemonstrate that these different limbic pathways are involved, it ispossible to lesion or inactivate (e.g., using optogenetic methods orlocal drugs) those regions and show that less or no plasticity changesoccur in the auditory system. These experiments can be conducted intinnitus animals to confirm that abnormal tinnitus patterns can besuppressed or reversed to eliminate behavioral tinnitus. Since thetreatment approaches are noninvasive and use safe methods, the findingscan be confirmed from these animal studies directly in humans bymonitoring the tinnitus percept while implementing differentcombinations of parameters.

Direct brain stimulation (DBS) to treat various neurological disordershas become more widely accepted over the past decade due to its success,especially for tremor suppression in Parkinson's and Essential Tremorpatients. However, it still requires invasive surgery and can only bejustified in a small patient population. For tinnitus, there have beenattempts at stimulating the cortex, midbrain, brainstem, and othernon-auditory deep brain structures, but only in patients withdebilitating conditions or who are already undergoing other types ofneurosurgical operations (e.g., epilepsy surgery, tumor removal). Totreat a larger population, non-invasive methods have been investigated.Previous methods attempt to modulate and drive precise plasticrestoration of the auditory system using non-invasive stimulation thatare not generally capable of precise or specific activation. Anpromising aspect of the methods described herein are that they activatea neural switch mechanism to reset the tinnitus-affected neurons back tonormal using precisely synchronized stimulation across multiple sitesrather than attempt to drive precise plasticity with continuous pulsestimulation (e.g., constant 100 Hz pulse train) on a given site. Atleast two brain regions, ICX and PPT, have been identified which can bestimulated to alter neural activity within the ICC and the centralauditory system. An important aspect, in certain embodiments, is tonon-invasively activate the ICX and/or PPT neural switch regions.Sufficient synchronized activity needs to be generated duringstimulation of ICX or PPT combined with sufficient acoustic activationto be successful. Fortunately, ICX and PPT (also CNX, MGX, otherreticular activating and limbic nuclei) receive converging andexcitatory projections from all over the head, face, ears, eyes, mouth,tongue, neck, body, limbs, and genital areas as well as from theauditory and somatosensory cortices (FIG. 1). As described herein, it ispossible to electrically activate these pathways non-invasively andsimultaneously through transcutaneous stimulation to elicit a neuralshock within the brain that activates the neural switch. It is possibleto position surface electrodes (e.g., 20, 100 or 1000) over the body andlimbs (e.g., feet, legs, shoulders, back, arms, fingers, genital areas)as well as the neck, pinna, cheeks, eye region, nose, tongue, teeth, andforehead. For safety, the goal is to use low level current on each sitebut across many sites to elicit a highly synchronous response in theneural switch regions. It is also possible to use non-invasive corticalstimulation (e.g., surface or transcranial magnetic stimulation) toactivate the descending cortical projections and shine light into theeye to activate optic nerve projections to contribute to the neuralshock. Smell and taste inputs are also able to project to overlappingbrain regions that would then activate these neural switch regions, andthus it is possible to provide scent and taste stimuli as well.

Transcutaneous stimulation in humans will be initially implemented.Other non-invasive techniques will also be assessed to activate the skinsurface and the corresponding nerve projections through vibration,pressure, heat, optics, or ultrasound. If more specificity andsynchronization is required in certain circumstances, minimally-invasivewireless electrodes may be implanted, e.g., subcutaneously or aroundspecific nerves. As an alternative, there are numerous invasive devicesalready in use and implanted in regions all over the brain that can beconsidered for eliciting sufficient shock stimulation throughsynchronized activation across all these different modalities.

The described treatment can provide a powerful way to noninvasivelymodulate tinnitus-affected neurons. It can also be implemented with lowcost hardware and surface electrodes that can be easily miniaturized forportability and take-home usage, expanding on transcutaneous electricalnerve stimulation (TENS) devices safely used for pain or massage therapy(e.g., 2-site devices <$50 can already be purchased in stores). In orderto investigate the numerous stimulation parameters directly in humansand identify the optimal settings, it is possible to pursue what istermed a heuristic translational approach. A low cost device can beimplemented that could be distributed across a large patient group andtaken home for continuous optimization by the patients. The simplestexample would be to have a digital device with a knob that can scrollthrough the different stimuli that are preset during the clinicalfitting session. The patient would input a rating into their device foreach setting that effectively reduces their tinnitus. The device wouldcontinue to adjust the stimulation parameters based on these ratings toconverge towards an optimal setting. Self-fitting through a heuristictranslational approach is how the treatment can be fitted across a largenumber of patients and stimulation parameters. The patients are able toinvest a considerable amount of time optimizing their own device. Anysigns of improvement in their tinnitus with this treatment will providesignificant motivation for the patients to continue optimizing their owndevice. Another advantage of a heuristic translational approach is thatit is not necessary to understand the neural mechanisms of each type oftinnitus to improve the treatment. Instead, the device is heuristicallyoptimized for each patient, which can overcome the issue of patientvariability. The patients could also connect to an online server anddatabase in which they can download new software for their device aswell as upload their device parameters and progress. This onlineinteraction with the patients would allow collection an enormous amountof data across a large population to identify appropriate stimulationpatterns for different types of tinnitus patients. The patients can alsointeract with other patients and skilled personnel to help each other aswell as improve the tinnitus treatment.

An innovation of multimodal stimulation therapy (MST) is that it canpotentially achieve both specificity and noninvasiveness, and beoptimized using a heuristic translational approach. MST takes advantageof the dense and coordinated interconnectivity across sensory, motor,cognitive, and limbic centers. One center may exhibit abnormal activitydriving the neurological disorder. A goal of MST is to activate specificpathways related to the other modalities to then modulate and fix theabnormal region. This assumes that these different pathways can interactand induce plasticity across centers, which seems likely considering thenecessity of precise coordination and reinforcement among thesemodalities during daily function and survival. MST can be used fortinnitus suppression through coordinated activation of auditory andsomatosensory pathways. It is also possible to incorporate additionalreinforcement, such as visual cues, cognitive and emotional activation(e.g., through mental tasks or emotional visual scenes),reward/pleasurable input (e.g., aromatherapy or soothing bodysensations), or slightly painful stimuli. Another potential MSTapplication is the treatment of phantom limb pain. Analogous topresenting customized acoustic stimuli to activate specific auditoryneurons linked to tinnitus, specific parts of the phantom limb could bestimulated (e.g., using current, pressure, or temperature stimuli) andreinforced by activation of the other modalities. For cognitive oremotional disorders, the activation process may be more complex but theMST approach could still be effective. For example, if the patient has amemory or learning issue, cognitive tasks that are already used in thefield can be implemented. What is innovative about MST is that thesestandard tasks can be combined with activation of other modalities. Itis possible to provide coordinated body stimulation or even slightlypainful but comfortable electrical shocks on the body in combinationwith a task. Not only could this induce synchronized activation oftarget brain regions, but it would also lead to elevated states ofanxiety or excitement, naturally releasing neurotransmitters that couldenhance plasticity and reinforcement to the task.

Integrative Role of Inferior Colliculus Relevant for the Treatment

The inferior colliculus (IC) is the principal midbrain nucleus of theauditory pathway and receives input from several more peripheralbrainstem nuclei in the auditory pathway, as well as inputs from theauditory cortex. The inferior colliculus has three subdivisions: thecentral nucleus (ICC), a dorsal cortex by which it is surrounded, and anexternal cortex, which is located laterally. Its multimodal neurons areimplied in auditory-somatosensory interaction, receiving projectionsfrom somatosensory nuclei. The input connections to the inferiorcolliculus are composed of many brainstem nuclei. All nuclei except thecontralateral ventral nucleus of the lateral lemniscus send projectionsto the central nucleus bilaterally. It has been shown that a greatmajority of auditory fibers ascending in the lateral lemniscus terminatein the central nucleus. In addition, the IC receives inputs from theauditory cortex, the medial division of the medial geniculate body, theposterior limitans, suprapeduncular nucleus and subparafascicularintralaminar nuclei of the thalamus, the substantia nigra, pars compactalateralis, the dorsolateral periaqueductal gray, the nucleus of thebrachium of the inferior colliculus, deep layers of the superiorcolliculus, reticular activating nuclei, limbic nuclei, and othermodulatory centers. The inferior colliculus receives input from both theipsilateral and contralateral cochlear nucleus and respectively thecorresponding ears. The medial geniculate body is the output connectionfrom inferior colliculus and the last subcortical way station. Themedial geniculate body is composed of ventral, dorsal, and medialdivisions, which are relatively similar in humans and other mammals. Theventral division receives auditory signals from the central nucleus ofthe IC.

Certain embodiments of the invention will now be illustrated by thefollowing non-limiting Examples.

Example 1

The experiments described herein focus on plasticity experiments toconfirm that a dual fixed-plastic representation exists for featuresrelating to tinnitus, such as tonotopy, firing rates, synchrony, andbursting. Other experiments involve direct stimulation of ICX, CNX, MGX,reticular activating nuclei, and limbic centers to assess the neuralswitch effect within the ICC, CNV, MGV, and A1 in normal hearing andtinnitus animals. Other experiments identify the non-auditoryprojections that can be simultaneously activated with subcutaneouselectrical stimulation or surface manipulation (e.g., pressure, gentlestroking, air puffs, pinching) to elicit a synchronous response in thedifferent neural switch regions and to suppress tinnitus-driving neuronswithin the central auditory system.

The plasticity experiments will use earplugs that will predominantlyattenuate high frequencies. These can be used in guinea pigs, and laterin humans, to create a temporary high frequency hearing loss. Unliketraditional methods of permanently damaging the peripheral auditorysystem through noise, drugs, or mechanical manipulations, the earplugscan be inserted and removed to reversibly alter the hearing condition.High frequency hearing loss situations can be induced that allow thebrain to reorganize in terms of tonotopy and firing patterns acrossneurons. The earplugs can then be removed, and acoustic stimulationpresented to accurately characterize the neurons within the CNV, ICC,MGV, and A1, which is not possible with traditional deafening methods.More importantly, to demonstrate the dual fixed-plastic representationwithin the brain, it is possible to re-expose the animal to naturalsounds by removing the ear plugs and show that the original tonotopy andfiring patterns return quite quickly. The earplugs can also bere-inserted and removed repeatedly to assess how quickly and accuratelythe brain switches back and forth between brain states. The animals willbe implanted chronically with electrode arrays or a special chamber toallow arrays to be re-inserted at different time points. Several headscrews will also be implanted on the skull to allow non-invasiveconnection for EEG recordings to more frequently monitor the plasticchanges over time. Using this creative earplug paradigm, all thedifferent neural switch regions can be electrically stimulated andassessed to switch the brain back and forth between the original andreorganized states.

It is possible to induce tinnitus in guinea pigs using two commonmethods relevant for the types of tinnitus observed in humans: (1) loudnoise exposure, and (2) ototoxic drugs (e.g., salicylate). Chronicelectrode arrays (e.g., 32-64 site arrays) can then be implanted intodifferent auditory and neural switch regions. A special chamber will beimplanted on the skull for re-inserting arrays with degraded recordings.Tinnitus in animals will be assessed before and after the synchronizedstimulation paradigm, and also determine the duration and stability ofsuppression over repeated stimulus presentations. The neural activityand electrode site locations based on histological brain reconstructionswill be correlated with the perceptual effects.

Ultimately, this therapy will be used in humans to suppress a phantompercept across a wide range of patients, such as tinnitus patients. Aphantom percept refers to the conscious awareness of a percept in theabsence of an external stimulus. Examples of phantom percepts aretinnitus and phantom limb (e.g., phantom limb pain). The treatment willbe tested across a large range of tinnitus animals and the perceptualeffect will be behaviorally confirmed. The startle response will be usedto assess tinnitus perception in animals. This is a creative methoddeveloped by Turner and colleagues at Southern Illinois University thatdoes not require time consuming animal training but is based on a simplereflex response. A loud unexpected sound burst will cause an animal tostartle and can be measured with a force plate. If a soft short sound(or short gap in a continuously played soft sound) precedes this loudsound (i.e., the pre-burst stimulus), it reduces the animal's startleresponse. If an animal has tinnitus, the pre-burst stimulus can bealigned with and masked by the tinnitus percept. In this case, animalswith tinnitus will not have a reduced startle response to the pre-burststimulus. The startle response method has been used successfully bynumerous researchers worldwide.

By synchronizing the electrical shock with acoustic stimulation, longlasting enhancement or suppression of firing activity can be inducedthat is highly dependent on the delay between the stimuli. Impropertiming could worsen (enhance) rather than suppress the tinnitus.Non-invasive evoked EEG activity will be used to monitor the stimulationeffects since it is designed to record synchronous activity and can becorrelated with direct recordings of the different auditory and neuralswitch regions. In patients, an automated algorithm can be used thatwould stimulate across different combinations of sites with varyingdelays until the largest EEG response was elicited with an appropriatepattern across recording sites, indicating a highly synchronous shockwithin the appropriate brain region. The number of EEG electrode sitesand locations as well as activation pattern will initially be based onfindings from animals. The time delay for the electrical shock alone andthe acoustic stimulus alone to each reach the neural switch region basedon the evoked EEG response latency will be measured. Based on thesetimings, the algorithm would determine the appropriate delay between thesynchronized acoustic and electrical stimuli to suppress rather thanenhance the tinnitus. This algorithm will be used to ensure itidentifies the appropriate parameters within a reasonable time period.Fortunately, each EEG response can be collected quite quickly (<100 ms).

A subjective approach that will run in parallel with the objective EEGapproach is also to create a user interface that allows the subject toscroll through the different parameters. There will be a large parameterspace. However, it is possible to scroll through a subset of parametersand then select the few that can affectively alter and improve thetinnitus percept. Then the interface determines the next best parametersbased on the past successful parameters. Through continued use anditerations of this algorithm, the interface will be able to identify theoptimal parameters over time. This would involve development of low costtechnologies and stimulators that can be easily positioned all over thebody and head and intuitive to use across a large patient population.The device would also be connected to the internet to allow real-timedata collection, analyses, and feedback to make parameter identificationmore efficient. The data would be collected across a large patientpopulation and can then be rapidly collected and assessed for whichparameters work most effectively for the different tinnitus types. Inturn, these data would guide the initial parameter space for eachproceeding subject. Therefore, a new heuristic approach to performingtranslational research directly in humans is proposed using non-invasivestrategies, internet technologies (e.g., online programs, databases, andsmart apps), and parameter optimization/assessment performed by thepatients themselves.

Example 2. Unpredictability Based Method for Treating Tinnitus and OtherNeurological Disorders

This approach is based on similar concepts as the multimodal stimulationtherapy (MST) approach in that it shifts brain regions linked totinnitus to suppress the phantom percept (and relevant to otherneurological disorders with similar types of “bad” plasticity). In theMST, synchronized stimulation across multiple body and head regions isused to elicit synchronized shocks in both auditory and non-auditorybrain regions to shift plasticity back to normal. One of the featuresfor the MST therapy is the ability to activate specific brain regions(e.g., limbic and arousal centers) that can then reinforce thesimultaneous acoustic driven activity that could suppress the tinnituspercept. Another feature of MST is the ability to achieve these effectswith non-invasive stimulation. In the approach described in thisexample, which is termed “Unpredictability-based Stress and AnxietyResponse therapy (USAR Therapy), acoustic stimulation is still presentedas well as the option to perform MST. However, an additional innovativeaspect of the USAR therapy is that the limbic and arousal centers areactivated, e.g., using a behavioral approach. The creative idea is toprovide a painful yet acceptable electrical stimulus to different partsof the body (or any other type of painful or startle stimulus, such as aloud sound burst or scary visual image or pinch). A key feature is thatthe tinnitus patient does not know when or where this stimulus will bepresented. This unpredictability and uncertainty will put the patientinto a stressful and anxious state. This in turn will activate multiplelimbic, arousal, and attentive centers and release a wide range ofhormones and neurotransmitters involved with plasticity andreinforcement. This release itself is not sufficient to treat thetinnitus, though it could alter the tinnitus percept as has been shownwith various drugs. An important component is to present acousticstimuli synchronized to this painful stimulus to reinforce thoseacoustic inputs. One scenario would be to play all frequencies exceptthe main frequency component of the tinnitus which would in turnreinforce all the other stimuli to begin to dominate the tinnitusstimulus component. This would begin to suppress the dominance of thetinnitus percept. Another scenario is to present randomized acousticstimuli spanning across a wide range of features, even the tinnitusfeatures that would desynchronize and dilute the specific effects of thetinnitus percept. It is possible to use drugs to release hormones andneurotransmitters and then present acoustic stimuli as well as the MSTto treat tinnitus. However, in this drug-based scenario, there is noprecisely timed reinforcement of the drug effects with the acoustic andelectrical stimulation. By inducing anxiety and stress with thisunpredictable and painful stimulus, the patient's brain will not only beexposed to these different hormones and neurotransmitters, but will alsorelease these chemical that can be synchronized to the painful stimulusthat provides a precise manner to shift the brain back to normal,optionally in combination with MST. Furthermore, this approach does notrely on introducing any potentially harmful substance into the body butuses the body's own hormones and neuro-chemicals to achieve the effectwhile also being non-invasive. The device would consist of similarcomponents as the MST except that one site (or several sites) would bestimulated with a painful stimulus. The patient can be focusing on ascreen to indicate that a painful stimulus will be presented within aspecific time period (e.g., 30 s) that at least provides someorganizational information to the patient (i.e., the patient knows whatto be doing at a certain time) and is also a way to systematically alterthe patients attention and interactions with the treatment (e.g., apatient performs a task during this paradigm to distract or increasefocus on the painful stimulus that could vary the overall reinforcementeffect). Since the anxiety and stress, and thus the neuro-chemical,induced by the USAR therapy will adapt over time (i.e., become weakerwith repeated stimulation), it will be important to provide on and offperiods of treatment. It will also be important to alter the sites andpattern of unpredictability to continue to release the necessaryneuro-chemicals for longer periods of time. These effects can be variedby altering the stimulation strategies as well as the type of pain orstartle stimulus used.

This approach may be applied to other neurological disorders thatinvolve abnormal plastic states. This can be a significant opportunityto treat an even larger patient population, such as those experiencingpain or even cognitive/emotional changes. For example, for someoneexperiencing phantom pain, there would be changes in the somatosensorysystem. This system also receives multi-modal inputs and processing. Inthis case, an unpredictable and loud startle sound stimulus and/ordisturbing visual image can be presented and combined that withsomatosensory body stimulation. This could also be combined with MST.Another example would be someone experiencing a learning or cognitivedeficit. That person could perform a mental task combine with USARTherapy and MST to reinforce the neurons related to that task andenhance learning or cognitive capacity.

These findings are surprising in many respects because it is actuallycounterintuitive to attempt to induce stress and anxiety to suppresstinnitus because tinnitus induction is usually associated with greaterstress and anxiety. However, the logic is based on synchronizingappropriate activation of specific auditory and non-auditory regions tothis painful/startle stimulus to increase the dominance of other soundcomponents that would dilute the contribution of the tinnitus soundcomponent (i.e., so make the brain more sensitive and attentive to othersound components and thus making it relatively less sensitive to thetinnitus component). Alternatively, this approach could activatemultiple neurons, including those representing the tinnitus percept, tothen drive desynchronization and plasticity across those neurons toeliminate the phantom percept.

Example 3: Mapping the Inferior Colliculus

Applicants have conducted experiments demonstrating that neurons alongthe dorsal region of the IC code for different body regions in aspatially-ordered pattern. It was found that upper body regionsgenerally activate more lateral regions of the IC while lower bodyregions generally activate more medial IC regions. It was found thatleft body regions activate more rostral-medial regions compared to thosefor the right body regions. Overall, it was found that the toe-to-headbody orientation is superimposed onto the caudal-medial torostral-lateral axis of the IC. There are also overlapping regions of ICthat are activated by different body sites and with varying delays.Therefore, based in part on this work, specific regions of the IC can beactivated by stimulating the appropriate body sites with the appropriatedelays.

All documents cited herein are incorporated by reference. While certainembodiments of invention are described, and many details have been setforth for purposes of illustration, certain of the details can be variedwithout departing from the basic principles of the invention.

The use of the terms “a” and “an” and “the” and similar terms in thecontext of describing embodiments of invention are to be construed tocover both the singular and the plural, unless otherwise indicatedherein or clearly contradicted by context. The terms “comprising,”“having,” “including,” and “containing” are to be construed asopen-ended terms (i.e., meaning “including, but not limited to”) unlessotherwise noted. Recitation of ranges of values herein are merelyintended to serve as a shorthand method of referring individually toeach separate value falling within the range, unless otherwise indicatedherein, and each separate value is incorporated into the specificationas if it were individually recited herein. In addition to the orderdetailed herein, the methods described herein can be performed in anysuitable order unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g., “such as”) provided herein, is intended merely to betterilluminate embodiments of invention and does not necessarily impose alimitation on the scope of the invention unless otherwise specificallyrecited in the claims. No language in the specification should beconstrued as indicating that any non-claimed element is essential to thepractice of the invention.

1-49. (canceled)
 50. A method, comprising: delivering to a subject atleast one synchronized stimulation, wherein the synchronized stimulationcomprises an effective delivery of synchronized stimulation to thesubject from at least one auditory neuronal pathway synchronized withstimulation from at least one non-auditory neuronal pathway, wherein thedelivery of stimulation to the at least one auditory neuronal pathwayand the stimulation to the at least one non-auditory neuronal pathway issynchronized for delivery via a device.
 51. The method of claim 50,wherein the at least one non-auditory neuronal pathway is asomatosensory neuronal pathway.
 52. The method of claim 50, wherein theat least one non-auditory neuronal pathway is a pathway associated withat least one of a patient's head, face, ear, eye, nose, mouth, lip,tongue, tooth, neck, body, limb, genital areas, buttocks/anus regions,hand, finger, foot, or toe.
 53. The method of claim 52, wherein thesynchronized stimulation comprises stimulation of multiple non-auditoryneuronal pathways associated with at least two different body locationsof the at least one of the patient's head, face, ear, eye, nose, mouth,lip, tongue, tooth, neck, body, limb, genital areas, buttocks/anusregions, hand, finger, foot, or toe.
 54. The method of claim 50, whereinthe subject has a neurological disorder comprising at least one of bodytremors, pain, phantom percept, phantom limb pain, motor deficits,hyperacusis, tinnitus, or a psychological disorder or mental disorder.55. The method of claim 54, wherein the psychological disorder or mentaldisorder is at least one of an obsessive compulsive disorder,depression, stress, a memory or learning disability, a speechimpediment, a visual hallucination, or an auditory hallucination. 56.The method of claim 50, wherein the synchronized stimulation includesmultiple discrete synchronized stimulations in a stimulus patternlasting up to 1 second for each activated pathway with a specificallydetermined time between each activated pathway that ranges between0-1000 ms.
 57. The method of claim 50, wherein the synchronizedstimulation comprises stimulation that induces at least one of anxietyor stress in the patient.
 58. The method of claim 50, wherein thestimulation from the at least one non-auditory neuronal pathway isevoked by at least one of non-invasive stimulation, vibration, pressure,heat, optics, magnetic, ultrasound, taste, scent stimulation ortranscutaneous electrical stimulation.
 59. The method of claim 50,wherein the synchronized stimulation is provided by surface electrodes.60. A method, comprising: delivering to a subject at least onesynchronized stimulation, wherein the synchronized stimulation comprisesan effective delivery of synchronized stimulation to the subject from atleast two body locations, wherein the delivery of stimulation to the atleast two body locations is synchronized for delivery via a device. 61.The method of claim 60, wherein the synchronized stimulation is appliedto a somatosensory neuronal pathway.
 62. The method of claim 60, whereinthe synchronized stimulation is applied to a pathway associated with atleast one of the patient's head, face, ear, eye, nose, mouth, lip,tongue, tooth, neck, body, limb, genital areas, buttocks/anus regions,hand, finger, foot, or toe.
 63. The method of claim 62, wherein thesynchronized stimulation comprises stimulation of multiple non-auditoryneuronal pathways associated with at least two different body locationsof the at least one of the patient's head, face, ear, eye, nose, mouth,lip, tongue, tooth, neck, body, limb, genital areas, buttocks/anusregions, hand, finger, foot, or toe.
 64. The method of claim 60, whereinthe subject has a neurological disorder comprising at least one of bodytremors, pain, phantom percept, phantom limb pain, motor deficits,hyperacusis, tinnitus, or a psychological disorder or mental disorder.65. The method of claim 64, wherein the psychological disorder or mentaldisorder is at least one of an obsessive compulsive disorder,depression, stress, a memory or learning disability, a speechimpediment, a visual hallucination, or an auditory hallucination. 66.The method of claim 60, wherein the synchronized stimulation includesmultiple discrete synchronized stimulations in a stimulus patternlasting up to 1 second for each activated pathway with a specificallydetermined time between each activated pathway that ranges between0-1000 ms.
 67. The method of claim 60, wherein the synchronizedstimulation comprises stimulation that induces at least one of anxietyor stress in the patient.
 68. The method of claim 60, wherein thestimulation from the at least one non-auditory neuronal pathway isevoked by at least one of non-invasive stimulation, vibration, pressure,heat, optics, magnetic, ultrasound, taste, scent stimulation ortranscutaneous electrical stimulation.
 69. A method, comprising:delivering to a subject at least one synchronized stimulation, whereinthe synchronized stimulation comprises an effective delivery ofsynchronized stimulation to the subject from an acoustic stimulationsynchronized with a non-invasive synchronized stimulation of a vibrationto at least one body location, wherein the delivery of stimulation tothe at least one body location is synchronized for delivery via adevice.